Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population.

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Visual and audiovisual effects of isochronous timing on visual perception and brain activity

Understanding how the brain extracts and combines temporal structure (rhythm) information from events presented to different senses remains unresolved. Many neuroimaging beat perception studies have focused on the auditory domain and show the presence of a highly regular beat (isochrony) in "auditory" stimulus streams enhances neural responses in a distributed brain network and affects perceptual performance. Here, we acquired functional magnetic resonance imaging (fMRI) measurements of brain activity while healthy human participants performed a visual task on isochronous versus randomly timed "visual" streams, with or without concurrent task-irrelevant sounds. We found that visual detection of higher intensity oddball targets was better for isochronous than randomly timed streams, extending previous auditory findings to vision. The impact of isochrony on visual target sensitivity correlated positively with fMRI signal changes not only in visual cortex but also in auditory sensory cortex during audiovisual presentations. Visual isochrony activated a similar timing-related brain network to that previously found primarily in auditory beat perception work. Finally, activity in multisensory left posterior superior temporal sulcus increased specifically during concurrent isochronous audiovisual presentations. These results indicate that regular isochronous timing can modulate visual processing and this can also involve multisensory audiovisual brain mechanisms

Plasma REST: A novel candidate biomarker of Alzheimer\u27s disease is modified by psychological intervention in an at-risk population

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain’s stress response. It is reduced in conditions of stress and Alzheimer’s disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention—mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Relationship between Activity in Human Primary Motor Cortex during Action Observation and the Mirror Neuron System

The attenuation of the beta cortical oscillations during action observation has been interpreted as evidence of a mirror neuron system (MNS) in humans. Here we investigated the modulation of beta cortical oscillations with the viewpoint of an observed action. We asked subjects to observe videos of an actor making a variety of arm movements. We show that when subjects were observing arm movements there was a significant modulation of beta oscillations overlying left and right sensorimotor cortices. This pattern of attenuation was driven by the side of the screen on which the observed movement occurred and not by the hand that was observed moving. These results are discussed in terms of the firing patterns of mirror neurons in F5 which have been reported to have similar properties

Means and covariance functions for geostatistical compositional data: an axiomatic approach

This work focuses on the characterization of the central tendency of a sample of compositional data. It provides new results about theoretical properties of means and covariance functions for compositional data, with an axiomatic perspective. Original results that shed new light on the geostatistical modeling of compositional data are presented. As a first result, it is shown that the weighted arithmetic mean is the only central tendency characteristic satisfying a small set of axioms, namely continuity, reflexivity and marginal stability. Moreover, this set of axioms also implies that the weights must be identical for all parts of the composition. This result has deep consequences on the spatial multivariate covariance modeling of compositional data. In a geostatistical setting, it is shown as a second result that the proportional model of covariance functions (i.e., the product of a covariance matrix and a single correlation function) is the only model that provides identical kriging weights for all components of the compositional data. As a consequence of these two results, the proportional model of covariance function is the only covariance model compatible with reflexivity and marginal stability

The Global Risk Approach Should Be Better Applied in French Hypertensive Patients: A Comparison between Simulation and Observation Studies

The prediction of the public health impact of a preventive strategy provides valuable support for decision-making. International guidelines for hypertension management have introduced the level of absolute cardiovascular risk in the definition of the treatment target population. The public health impact of implementing such a recommendation has not been measured.We assessed the efficiency of three treatment scenarios according to historical and current versions of practice guidelines on a Realistic Virtual Population representative of the French population aged from 35 to 64 years: 1) BP≥160/95 mm Hg; 2) BP≥140/90 mm Hg and 3) BP≥140/90 mm Hg plus increased CVD risk. We compared the eligibility following the ESC guidelines with the recently observed proportion of treated amongst hypertensive individuals reported by the Etude Nationale Nutrition Santé survey. Lowering the threshold to define hypertension multiplied by 2.5 the number of eligible individuals. Applying the cardiovascular risk rule reduced this number significantly: less than 1/4 of hypertensive women under 55 years and less than 1/3 of hypertensive men below 45 years of age. This was the most efficient strategy. Compared to the simulated guidelines application, men of all ages were undertreated (between 32 and 60%), as were women over 55 years (70%). By contrast, younger women were over-treated (over 200%).The global CVD risk approach to decide for treatment is more efficient than the simple blood pressure level. However, lack of screening rather than guideline application seems to explain the low prescription rates among hypertensive individuals in France. Multidimensional analyses required to obtain these results are possible only through databases at the individual level: realistic virtual populations should become the gold standard for assessing the impact of public health policies at the national level

From threat to fear: the neural organization of defensive fear systems in humans

Postencounter and circa-strike defensive contexts represent two adaptive responses to potential and imminent danger. In the context of a predator, the postencounter reflects the initial detection of the potential threat, whereas the circa-strike is associated with direct predatory attack. We used functional magnetic resonance imaging to investigate the neural organization of anticipation and avoidance of artificial predators with high or low probability of capturing the subject across analogous postencounter and circa-strike contexts of threat. Consistent with defense systems models, postencounter threat elicited activity in forebrain areas, including subgenual anterior cingulate cortex (sgACC), hippocampus, and amygdala. Conversely, active avoidance during circa-strike threat increased activity in mid-dorsal ACC and midbrain areas. During the circa-strike condition, subjects showed increased coupling between the midbrain and mid-dorsal ACC and decreased coupling with the sgACC, amygdala, and hippocampus. Greater activity was observed in the right pregenual ACC for high compared with low probability of capture during circa-strike threat. This region showed decreased coupling with the amygdala, insula, and ventromedial prefrontal cortex. Finally, we found that locomotor errors correlated with subjective reports of panic for the high compared with low probability of capture during the circa-strike threat, and these panic-related locomotor errors were correlated with midbrain activity. These findings support models suggesting that higher forebrain areas are involved in early-threat responses, including the assignment and control of fear, whereas imminent danger results in fast, likely "hard-wired," defensive reactions mediated by the midbrain

Trends in Weekly Reported Net use by Children During and after Rainy Season in Central Tanzania.

The use of long-lasting insecticidal nets (LLINs) is one of the principal interventions to prevent malaria in young children, reducing episodes of malaria by 50% and child deaths by one fifth. Prioritizing young children for net use is important to achieve mortality reductions, particularly during transmission seasons. Households were followed up weekly from January through June 2009 to track net use among children under seven under as well as caretakers. Net use rates for children and caretakers in net-owning households were calculated by dividing the number of person-weeks of net use by the number of person-weeks of follow-up. Use was stratified by age of the child or caretaker status. Determinants of ownership and of use were assessed using multivariate models. Overall, 60.1% of the households reported owning a bed net at least once during the study period. Among net owners, use rates remained high during and after the rainy season. Rates of use per person-week decreased as the age of the child rose from 0 to six years old; at ages 0-23 months and 24-35 months use rates per person-week were 0.93 and 0.92 respectively during the study period, while for children ages 3 and 4 use rates per person-week were 0.86 and 0.80. For children ages 5-6 person-week ratios dropped to 0.55. This represents an incidence rate ratio of 1.67 for children ages 0-23 months compared to children aged 5-6. Caretakers had use rates similar to those of children age 0-35 months. Having fewer children under age seven in the household also appeared to positively impact net use rates for individual children. In this area of Tanzania, net use is very high among net-owning households, with no variability either at the beginning or end of the rainy season high transmission period. The youngest children are prioritized for sleeping under the net and caretakers also have high rates of use. Given the high use rates, increasing the number of nets available in the household is likely to boost use rates by older children

Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4

The small ubiquitin-like modifier (SUMO) can form polymeric chains that are important signals in cellular processes such as meiosis, genome maintenance and stress response. The SUMO-targeted ubiquitin ligase RNF4 engages with SUMO chains on linked substrates and catalyses their ubiquitination, which targets substrates for proteasomal degradation. Here we use a segmental labelling approach combined with solution nuclear magnetic resonance (NMR) spectroscopy and biochemical characterization to reveal how RNF4 manipulates the conformation of the SUMO chain, thereby facilitating optimal delivery of the distal SUMO domain for ubiquitin transfer

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA